Synthesis of functionalised azepanes and piperidines from ...c Department of Organic Chemistry, Faculty of Chemistry, University of Łódź, Tamka 12, Łódź 91-403, Poland Experimental

− 1 −

Synthesis of functionalised azepanes and piperidines

from bicyclic halogenated aminocyclopropane derivatives

Cheng Chen,a Pullaiah Kattanguru,

a Olesya A. Tomashenko,

a,b Rafał Karpowicz,

a,c

Gabriela Siemiaszko,a Ahanjit Bhattacharya,

a Vinícius Calasans

a and Yvan Six

a*

a Laboratoire de Synthèse Organique (LSO), UMR 7652 CNRS / ENSTA / École Polytechnique,

Université Paris-Saclay, 91128 Palaiseau Cedex, France. b Saint Petersburg State University, Institute of Chemistry,7/9 Universitetskaya nab., St. Petersburg, 199034 Russia c Department of Organic Chemistry, Faculty of Chemistry, University of Łódź, Tamka 12, Łódź 91-403, Poland

Experimental procedures

I. Preparation of the cyclopropane substrates .............................................................................................. 2

II. Preparation of the cyclopropylammonium salts ..................................................................................... 14

III. Transformations of the haloaminocyclopropane salts .......................................................................... 18

General information: Methylmagnesium bromide (3.0 M solution in Et2O) and sec-butyllithium

(1.3−1.4 M solution in cyclohexane) were purchased from Sigma-Aldrich or Alfa Aesar and

titrated according to literature methods.1,2

Tetrahydrofuran, diethyl ether, dichloromethane,

toluene and methanol were purified using a MB SPS-800 solvent purification system

(MBRAUN). Other solvents and commercial reagents were used as received, without

purification. Petroleum ether refers to the 40−60 °C fraction. The microwave-promoted

experiments were run using a CEM Discover Microwave Synthesis System with the temperature

and time parameters indicated; the reaction vessels were not flushed with an inert gas. All other

reactions were carried out under nitrogen or argon. The temperatures mentioned are the

temperatures of the cold baths or the oil baths used. Flash column chromatography was

performed on VWR Chemicals or Merck silica gel 60 (40–63 μm). Concentration under reduced

pressure was carried out using rotary evaporators at 40 °C. NMR spectra were recorded with AM

400 or AVANCE 400 Bruker spectrometers (1H at 400.2 MHz,

13C at 100.6 MHz.

1− H.-S. Lin, L. A. Paquette, Synth. Comm. 1994, 24, 2503–2506.

2− W. G. Kofron, L. M. Baclawski, J. Org. Chem. 1976, 41, 1879–1880.

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry.This journal is © The Royal Society of Chemistry 2017

− 2 −

I. Preparation of the cyclopropane substrates

General procedure A: cyclopropanation of N-Boc dihydropyrroles

and N-Boc tetrahydropyridines with dichlorocarbene.3

10 M NaOH aqueous solution (20 mL) was slowly added to a solution of N-Boc cyclic enamine

substrate 1 (1.00 equiv, 3.50 mmol) and benzyltriethylammonium chloride (0.63 equiv,

2.20 mmol) in CHCl3 (20 mL). After 90−180 min of vigorous stirring at 20 °C, the aqueous

phase was removed. The organic layer was washed with H2O (20 mL) and brine (20 mL), then

dried over MgSO4, filtered and concentrated under reduced pressure to afford the crude product,

which was then purified by flash column chromatography on silica gel.

tert-Butyl 6,6-dichloro-2-azabicyclo[3.1.0]hexane-2-carboxylate 2a

a) Installation of the Boc group

tert-Butyl 2-oxopyrrolidine-1-carboxylate was prepared in 86−96% yield from 2-pyrrolidinone

(25.0 mmol) by applying a literature procedure.4

b) Reduction of the carbonyl group

Run 1: DIBAL-H (1.0 M in toluene, 1.50 equiv, 15.0 mmol, 15.0 mL) was added dropwise, at

−78 °C, to a solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (1.00 equiv, 10.0 mmol,

1.85 g) in dry THF (40 mL). After 5 h of stirring at −78 °C, Rochelle salt aqueous solution

(20 mL) was slowly added and the mixture was allowed to warm to 20 °C, with stirring until two

clear phases were formed. The organic phase was separated and the aqueous layer was extracted

with EtOAc (2 × 20 mL). The combined organic phases were dried over MgSO4, filtered and

concentrated under reduced pressure to afford a yellow oil. Analysis by 1H NMR spectroscopy

showed that this crude product contained essentially pure tert-butyl 2-hydroxypyrrolidine-1-

carboxylate (1.75 g, 9.35 mmol, 93%).5

3− Adapted from I. Lantos, D. Bhattacharjee, D. S. Eggleston, J. Org. Chem. 1986, 51, 4147−4150.

4− L. Banfi, A. Basso, V. Cerulli, G. Guanti, R. Riva, J. Org. Chem. 2008, 73, 1608−1611 (supporting information).

5− Procedure adapted from: R. K. Dieter, R. R. Sharma, J. Org. Chem. 1996, 61, 4180–4184.

− 3 −

Runs 2 and 3: The same reaction was run on 2.50 mmol and 5.00 mmol scale to produce,

respectively, 415 mg (2.22 mmol, 89%) and 886 mg (4.73 mmol, 95%) of tert-butyl

2-hydroxypyrrolidine-1-carboxylate.

c) Dehydration

Run 1: A solution of tert-butyl 2-hydroxypyrrolidine-1-carboxylate (1.00 equiv, 2.22 mmol,

415 mg) and para-toluenesulfonic acid monohydrate (0.19 mol%, 4.3 μmol, 1.0 mg) in toluene

(10 mL) was heated at reflux with a Dean-Stark apparatus for 1 h. After cooling, two drops of

Et3N were added and the solvent was removed under reduced pressure. The residue was

dissolved in EtOAc (20 mL), washed with H2O (2 × 10 mL) and brine (10 mL), then dried over

MgSO4, filtered and concentrated under reduced pressure to afford pure tert-butyl 2,3-

dihydropyrrole-1-carboxylate 1a as a yellow oil (279 mg, 1.65 mmol, 74%).


1.75 g) and para-toluenesulfonic acid monohydrate (0.17 mol%, 16 μmol, 3.0 mg) in toluene

(20 mL) was heated at reflux with a Dean-Stark apparatus for 4 h. After cooling, two drops of

Et3N were added and the solvent was removed under reduced pressure to afford a yellow oil

(1.15 g). Purification by flash column chromatography on silica gel (EtOAc / petroleum ether,

gradient from 0 to 5%) afforded pure 1a (950 mg, 5.61 mmol, 60%).


1.50 g) and para-toluenesulfonic acid monohydrate (0.32 mol%, 26 μmol, 5.0 mg) in toluene

(15 mL) was heated at reflux with a Dean-Stark apparatus for 18 h. After cooling, the solvent

was removed under reduced pressure to afford a yellow oil. Purification by flash column

chromatography on silica gel (EtOAc / petroleum ether, gradient from 0 to 30%) afforded

reasonably pure 1a (221 g, 1.31 mmol, 16%), contaminated with starting material, and fairly

pure tert-butyl 4-(1-tert-butoxycarbonylpyrrolidin-2-yl)-2,3-dihydropyrrole-1-carboxylate, little

useful in this context (882 mg, 2.61 mmol, 65%).

d) Cyclopropanation with dichlorocarbene

General procedure A was applied with 1a (1.00 equiv, 5.61 mmol, 950 mg). The crude product,

a yellow oil, was analysed by 1H NMR spectroscopy and found to contain fairly pure tert-butyl

6,6-dichloro-2-azabicyclo[3.1.0]hexane-2-carboxylate 2a (1.09 g, 4.32 mmol, 77%).

− 4 −

tert-Butyl 7,7-dichloro-2-azabicyclo[4.1.0]heptane-2-carboxylate 2b

■ Route 1: from piperidin-2-one


tert-Butyl 2-oxopiperidine-1-carboxylate was prepared in 69−92% yield from piperidin-2-one

(25.0 mmol) by applying a literature procedure.6

b) Reduction of the carbonyl group

DIBAL-H (1.0 M in hexanes, 1.50 equiv, 15.0 mmol, 15.0 mL) was added dropwise, at −78 °C,

to a solution of tert-butyl 2-oxopiperidine-1-carboxylate (1.00 equiv, 10.0 mmol, 1.99 g) in dry

THF (40 mL). After 2 h of stirring at −78 °C, Rochelle salt aqueous solution (20 mL) was slowly

added and the mixture was allowed to warm to 20 °C, with stirring until two clear phases were

formed. The organic phase was separated and the aqueous layer was extracted with EtOAc

(2 × 20 mL). The combined organic phases were dried over MgSO4, filtered and concentrated

under reduced pressure to afford a colourless oil (1.75 g). Analysis by 1H NMR spectroscopy

showed that this crude product contained a 67 : 33 mixture of tert-butyl 3,4-dihydro-2H-

pyridine-1-carboxylate 1b and tert-butyl 2-hydroxypiperidine-1-carboxylate.7,8

c) Dehydration

A solution of the mixture of tert-butyl 3,4-dihydro-2H-pyridine-1-carboxylate and tert-butyl 2-

hydroxypiperidine-1-carboxylate (1.75 g) and para-toluenesulfonic acid monohydrate

(0.26 mol%, 26 μmol, 5.0 mg) in toluene (15 mL) was heated at reflux with a Dean-Stark

apparatus for 30 minutes. After cooling, the solvent was removed under reduced pressure to

afford a yellow oil (1.50 g). Analysis by 1H NMR spectroscopy revealed that this crude product

contained virtually pure tert-butyl 3,4-dihydro-2H-pyridine-1-carboxylate 1b (1.50 g, 8.19

mmol, 82% over two steps).

6− T. M. Wilkinson, N. W. Stehle, P. Beak, Org. Lett. 2000, 2, 155−158 (supporting information).

7− Procedure adapted from: R. K. Dieter, R. R. Sharma, J. Org. Chem. 1996, 61, 4180–4184.

8− In another run performed under the same conditions on a 9 mmol scale, the crude product obtained, a yellow oil,

was found to contain pure tert-butyl 2-hydroxypiperidine-1-carboxylate (90% yield).

− 5 −

d) Cyclopropanation with dichlorocarbene

Run 1: General procedure A was applied with 1b (1.00 equiv, 4.83 mmol, 886 mg). The crude

product, a yellow oil, was analysed by 1H NMR spectroscopy and found to contain essentially

pure tert-butyl 7,7-dichloro-2-azabicyclo[4.1.0]heptane-2-carboxylate 2b (1.06 g, 3.98 mmol,

82%).

Run 2: General procedure A was applied with 1b (1.00 equiv, 5.46 mmol, 1.00 g). The crude

product, a yellow oil, was analysed by 1H NMR spectroscopy and found to contain essentially

pure 2b (1.32 g, 4.96 mmol, 91%).

■ Route 2: from piperidine


tert-Butyl piperidine-1-carboxylate was prepared in 95% yield from piperidine (172 mmol) by

applying a literature procedure.9

b) Kharasch-Sosnovsky reaction10

A flow of nitrogen was bubbled, for 15 min, through a mixture of tert-butyl piperidine-1-

carboxylate (1.25 equiv, 27.0 mmol, 5.00 g), copper(I) bromide (10% equiv, 2.16 mmol,

310 mg) and PhCl (0.10 L). The mixture was then heated to 90 °C (measured with a thermometer

plunged inside the flask) and a solution of tert-butyl peracetate (50 wt.% in mineral spirits,

1.00 equiv, 21.6 mmol, 5.71 g) in PhCl (50 mL) was slowly added (dropping funnel) over 3 h.

Stirring was then maintained at 90 °C overnight. After cooling, the mixture was concentrated

under reduced pressure and the residue (6.82 g) was analysed by 1H NMR spectroscopy to reveal

it contained a mixture of starting tert-butyl piperidine-1-carboxylate, tert-butyl 3,4-dihydro-2H-

pyridine-1-carboxylate 1b and tert-butyl 4-acetoxy-3,4-dihydro-2H-pyridine-1-carboxylate 1f in

a ratio of 68 : 23 : 09. This crude product was engaged in the next step without purification.

9− D. Stead, G. Carbone, P. O’Brien, K. R. Campos, I. Coldham, A. Sanderson, J. Am. Chem. Soc. 2010, 132,

7260−7261 (supporting information).

10− Procedure adapted from G. Sosnovsky, S.-O. Lawesson, Angew. Chem. 1964, 76, 218−225; Angew. Chem. Int.

Ed. 1968, 3, 269−276.

− 6 −

c) Cyclopropanation with dichlorocarbene

10 M NaOH aqueous solution (80 mL) was slowly added to a solution of the preceding mixture

(6.82 g) and benzyltriethylammonium chloride (0.52 equiv, 11.2 mmol, 2.55 g) in CHCl3

(80 mL). After 120 min of vigorous stirring at 20 °C, the organic phase was separated. the

aqueous layer was extracted with CHCl3 (3 × 20 mL). The combined organic phases (0.14 L)

were then washed with H2O (20 mL), dried over MgSO4, filtered and concentrated under

reduced pressure to afford the crude product (8 g). Purification by flash column chromatography

on silica gel (EtOAc / petroleum ether, gradient from 2 to 10%) afforded pure starting tert-butyl

piperidine-1-carboxylate (2.19 g, 11.8 mmol), tert-butyl 7,7-dichloro-2-

azabicyclo[4.1.0]heptane-2-carboxylate 2b (1.13 g, 4.25 mmol, 20% over two steps based on

tert-butyl peracetate; 28% over two steps based on non-recovered tert-butyl piperidine-1-

carboxylate) and tert-butyl (1R*,5R*,6R*)-5-acetoxy-7,7-dichloro-2-azabicyclo[4.1.0]heptane-2-

carboxylate 2f (628 mg, 1.94 mmol, 9% over two steps based on tert-butyl peracetate; 13% over

two steps based on non-recovered tert-butyl piperidine-1-carboxylate).

tert-Butyl 7,7-dibromo-2-azabicyclo[4.1.0]heptane-2-carboxylate 2c

■ Route 1: from piperidin-2-one

Run 1: 10 M NaOH aqueous solution (2.0 mL) was added dropwise to a solution of tert-butyl

3,4-dihydro-2H-pyridine-1-carboxylate 1b (prepared as indicated further above, 1.00 equiv,

350 μmol, 64.1 mg) and benzyltriethyl-ammonium chloride (0.63 equiv, 220 μmol, 50.2 mg) in

CHBr3 (1.0 mL). After 3 h 30 min of vigorous stirring at 20 °C, the aqueous phase was removed.

The organic layer was diluted with CH2Cl2 (10 mL), washed with brine (10 mL), then dried over

MgSO4, filtered and concentrated under reduced pressure to afford a yellow oil (920 mg).

Purification by flash column chromatography on silica gel (EtOAc / petroleum ether, gradient

from 0 to 10%) afforded pure tert-butyl 7,7-dibromo-2-azabicyclo[4.1.0]heptane-2-carboxylate

2c (84.0 mg, 236 μmol, 68%).

Run 2: 10 M NaOH aqueous solution (2.0 mL) was added dropwise to a solution of 1b

(prepared as indicated further above, 1.00 equiv, 600 μmol, 110 mg) and benzyltriethyl-

ammonium chloride (0.63 equiv, 378 μmol, 86.1 mg) in CHBr3 (2.0 mL). After 1 h of vigorous

stirring at 20 °C, the aqueous phase was removed. The organic layer was diluted with CH2Cl2

(10 mL), washed with H2O (10 mL) and brine (10 mL), then dried over MgSO4, filtered and

concentrated under reduced pressure to afford a brown oil (3.60 g). Purification by flash column

chromatography on silica gel (EtOAc / petroleum ether, gradient from 0 to 5%) afforded pure 2c

(161 mg, 453 μmol, 76%).

− 7 −

■ Route 2: from piperidine

a) Kharasch-Sosnovsky reaction10

A mixture of tert-butyl piperidine-1-carboxylate (prepared as indicated further above,

1.25 equiv, 27.6 mmol, 5.11 g), copper(I) bromide (10% equiv, 2.21 mmol, 317 mg) and PhCl

(20 mL) was heated at 100 °C for 15 min, then a solution of tert-butyl peracetate (50 wt.% in

mineral spirits, 1.00 equiv, 22.1 mmol, 5.83 g) in PhCl (40 mL) was added over 4 h (dropping

funnel). Stirring was then maintained at 100 °C for 1 h. After cooling, 0.1 M NaOH aq. solution

(40 mL) was added. The organic layer was separated, washed with H2O (2 × 20 mL), dried over

MgSO4, filtered and concentrated under reduced pressure to afford a dark yellow oil (5.73 g).

Analysis by 1H NMR spectroscopy revealed the crude product contained starting tert-butyl

piperidine-1-carboxylate, tert-butyl 3,4-dihydro-2H-pyridine-1-carboxylate 1b and tert-butyl 4-

acetoxy-3,4-dihydro-2H-pyridine-1-carboxylate 1f in a ratio of 69 : 20 : 11. This mixture was

engaged in the next step without further purification.

b) Cyclopropanation with dibromocarbene

10 M NaOH aqueous solution (10 mL) was slowly added to a solution of a part of the preceding

mixture (1.50 g) and benzyltriethylammonium chloride (0.52 equiv, 3.00 mmol, 683 mg) in

CHBr3 (10 mL). After 120 min of vigorous stirring at 20 °C, the organic phase was separated.

the aqueous layer was diluted with H2O (10 mL) and extracted with CH2Cl2 (20 mL). The

combined organic phases were dried over MgSO4, filtered and concentrated under reduced

pressure to afford a dark brown oil (2.51 g). Purification by flash column chromatography on

silica gel (EtOAc / petroleum ether, gradient from 1 to 20%) afforded pure tert-butyl 7,7-

dibromo-2-azabicyclo[4.1.0]heptane-2-carboxylate 2c (366 mg, 1.03 mmol, 18% over two steps

based on tert-butyl peracetate) and tert-butyl (1R*,5S*,6R*)-5-acetoxy-7,7-dibromo-2-

azabicyclo[4.1.0]heptane-2-carboxylate 2g (97.5 mg, 236 μmol, 4% over two steps based on tert-

butyl peracetate).

− 8 −

Relative configuration of the acetate group of 2f and 2g

Our assignment of the relative configuration of the acetate group of 2f and 2g is based on both

mechanistic considerations and 1H NMR data:

a) Mechanistic considerations

In a first analysis, the configuration of the acetate group being drawn as displayed below, attack

of the dichlorocarbene species from the bottom face should be kinetically favoured because of

steric effects.

b)

1H NMR data

The 3J coupling constant between H3 and H4 (numbering as in the drawing below) is easily

measured. Indeed, the signal of H4 is a doublet of doublets and identification of the two coupling

constants is straightforward, since the signal of H5 is a doublet giving the value of 3JH4-H5.

Comparison of these measured 3JH3-H4 coupling constants, in the major rotamers of 2f and 2g,

with estimated values obtained using generalised Karplus calculations11

strongly supports our

assignment, as shown in the Table below. The dihedral angles, for each possible

diastereoisomers of the two compounds, were measured on structures generated by PM7 semi-

empirical calculations12

using the MOPAC software.13

Calculated H3-H4

diehedral angle (PM7) −109° +20.3° −83.6° +22.8°

Calculated 3JH3-H4 1.5 Hz 7.7 Hz 1.1 Hz 7.5 Hz

Experimental 3JH3-H4 2.0 Hz 2.5 Hz

11− C.A.G. Haasnoot, F. A. A. M. de Leeuw, C. Altona, Tetrahedron 1980, 36, 2783−2792. On-line calculation

done at http://www.stenutz.eu/conf/haasnoot.php (accessed 14 March 2017).

12− J. J. P. Stewart, J. Mol. Mod. 2013, 19, 1−32.

13− MOPAC2016, Version: 16.035W, James J. P. Stewart, Stewart Computational Chemistry.

Web: http://OpenMOPAC.net.

− 9 −

tert-Butyl 6,6-dichloro-1-methyl-2-azabicyclo[3.1.0]hexane-2-carboxylate 2d

a) Addition of methylmagnesium bromide onto the carbonyl group

Run 1: Methylmagnesium bromide (3.0 M in Et2O, 1.40 equiv, 12.9 mmol, 4.29 mL) was added

dropwise, at 0 °C, to a solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (prepared as

indicated further above, 1.00 equiv, 9.18 mmol, 1.70 g) in dry THF (30 mL). The mixture was

stirred for 3 h while allowed to warm to 20 °C. H2O (10 mL) was then added. After filtration

through a short pad of celite, most of the THF was removed under reduced pressure. EtOAc

(50 mL) was then added. The organic layer was washed with saturated NaHCO3 aqueous

solution (2 × 20 mL) and brine (20 mL), then dried over MgSO4, filtered and concentrated under

reduced pressure. The crude product, a pale yellow oil, was analysed by 1H NMR spectroscopy

and found to contain pure tert-butyl N-(4-oxopentyl)carbamate (1.58 g, 7.85 mmol, 85%).


dropwise, at 0 °C, to a solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (prepared as


stirred at 0 °C for 4 h, then H2O (10 mL) was added. After filtration through a short pad of celite,

most of the THF was removed under reduced pressure. EtOAc (50 mL) was then added. The

organic layer was washed with saturated NaHCO3 aqueous solution (2 × 20 mL) and brine

(20 mL), then dried over MgSO4, filtered and concentrated under reduced pressure. The crude

product, a pale yellow oil, was analysed by 1H and

13C NMR spectroscopy and found to contain

pure tert-butyl N-(4-oxopentyl)carbamate (2.20 g, 10.9 mmol, 63%).

b) Dehydration

A solution of tert-butyl N-(4-oxopentyl)carbamate (1.00 equiv, 3.02 mmol, 608 mg) and para-

toluenesulfonic acid monohydrate (0.52 mol%, 16 μmol, 3.0 mg) in toluene (15 mL) was heated

at reflux with a Dean-Stark apparatus for 4 days. After cooling, the solvent was removed under

reduced pressure to afford a yellow oil (540 mg). Analysis by 1H NMR spectroscopy revealed

that this crude product contained virtually pure tert-butyl 5-methyl-2,3-dihydropyrrole-1-

carboxylate 1d (540 mg, 2.95 mmol, 98%).


General procedure A was applied with 1d (1.00 equiv, 2.95 mmol, 540 mg). The crude product,

a dark yellow oil (908 mg), was purified by flash column chromatography on silica gel (EtOAc /

petroleum ether, gradient from 0 to 10%) to afford pure tert-butyl 6,6-dichloro-1-methyl-2-

azabicyclo[3.1.0]hexane-2-carboxylate 2d (321 mg, 1.21 mmol, 41%).

− 10 −

tert-Butyl 7,7-dichloro-1-methyl-2-azabicyclo[4.1.0]heptane-2-carboxylate 2e

a) Addition of methylmagnesium bromide onto the carbonyl group


dropwise, at 0 °C, to a solution of tert-butyl 2-oxopiperidine-1-carboxylate (prepared as

indicated further above, 1.00 equiv, 3.00 mmol, 598 mg) in dry THF (10 mL). The cooling bath

was removed and the mixture was stirred at 20 °C for 19 h. H2O (3.0 mL) was then added. After

filtration through a short pad of celite, the mixture was dried over MgSO4, filtered and

concentrated under reduced pressure. The crude product, a yellow oil, was analysed by 1H NMR

spectroscopy and found to contain fairly pure tert-butyl N-(5-oxohexyl)carbamate (460 mg,

2.14 mmol, 71%).


dropwise, at 0 °C, to a solution of tert-butyl 2-oxopiperidine-1-carboxylate (prepared as


stirred at 0 °C for 5 h, then H2O (6.0 mL) was added. After filtration through a short pad of

celite, most of the THF was removed under reduced pressure. EtOAc (50 mL) was then added.

The organic layer was washed with saturated NaHCO3 aqueous solution (2 × 20 mL) and brine

(20 mL), then dried over MgSO4, filtered and concentrated under reduced pressure. The crude

product, a yellow oil, was analysed by 1H NMR spectroscopy and found to contain pure tert-

butyl N-(5-oxohexyl)carbamate (1.10 g, 5.11 mmol, 77%).

b) Dehydration

A solution of tert-butyl N-(5-oxohexyl)carbamate (1.00 equiv, 5.11 mmol, 1.10 g) and para-

toluenesulfonic acid monohydrate (0.50 mol%, 26 μmol, 5.0 mg) in toluene (15 mL) was heated

at reflux with a Dean-Stark apparatus. After 48 h, the solvent was removed under reduced

pressure to afford a yellow oil (1.10 g). Analysis by 1H NMR spectroscopy revealed that this

crude product contained essentially pure tert-butyl 6-methyl-3,4-dihydro-2H-pyridine-1-

carboxylate 1e (quantitative yield).


General procedure A was applied with 1e (1.00 equiv, 5.58 mmol, 1.10 g). The crude product,

a yellow oil (1.32 g), was purified by flash column chromatography on silica gel (EtOAc /

petroleum ether, gradient from 0 to 5%) to afford pure tert-butyl 7,7-dichloro-1-methyl-2-

azabicyclo[4.1.0]heptane-2-carboxylate 2e (540 mg, 1.93 mmol, 35%).

− 11 −

tert-Butyl (1R*,6S*,7R*)-7-chloro-2-azabicyclo[4.1.0]heptane-2-carboxylate exo-8

Run 1:

sec-Butyllithium solution (0.91 M in cyclohexane, 1.10 equiv, 1.10 mmol, 1.21 mL) was added

dropwise, at –78 °C, to a solution of tert-butyl 7,7-dichloro-2-azabicyclo[4.1.0]heptane-2-

carboxylate 2b (1.00 equiv, 1.00 mmol, 266 mg) and TMEDA (1.10 equiv, 1.10 mmol, 165 μL)

in Et2O (11 mL).14

After 15 minutes of stirring at –78 °C, H2O (20 mL) was added. The mixture

was then extracted with Et2O (3 × 20 mL). The combined organic layers were dried over MgSO4,

filtered and concentrated under reduced pressure to afford a pale yellow oil (237 mg). Analysis

of the crude product by 1H NMR spectroscopy showed that the starting material had been

entirely converted into tert-butyl 7-chloro-2-azabicyclo[4.1.0]heptane-2-carboxylate 8

[dr 59 : 41 in favour of the exo diastereoisomer]. Purification by two successive flash column

chromatographies on silica gel (EtOAc / petroleum ether, gradient from 2 to 10%) afforded pure

tert-butyl (1R*,6S*,7R*)-7-chloro-2-azabicyclo[4.1.0]heptane-2-carboxylate exo-8 (105 mg,

453 μmol, 45%), a 75 : 25 mixture of the endo and exo diastereoisomers of 8 (64.7 mg,

279 μmol, 28%) and pure tert-butyl (1R*,6S*,7S*)-7-chloro-2-azabicyclo[4.1.0]heptane-2-

carboxylate endo-8 (7.0 mg, 30 μmol, 3%).

Run 2:

sec-Butyllithium solution (0.91 M in cyclohexane, 1.10 equiv, 5.23 mmol, 5.75 mL) was added

dropwise, at –78 °C, to a solution of 2b (1.00 equiv, 4.76 mmol, 1.27 g) and TMEDA

(1.10 equiv, 5.23 mmol, 784 μL) in Et2O (50 mL).14

After 30 minutes of stirring at –78 °C, H2O

(50 mL) was added. The mixture was then extracted with Et2O (3 × 50 mL). The combined

organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to

afford a pale yellow oil (1.24 g). Analysis of the crude product by 1H NMR spectroscopy showed

that the starting material had been entirely converted into tert-butyl-7-chloro-2-

azabicyclo[4.1.0]heptane-2-carboxylate 8 [dr 63 : 37 in favour of the exo diastereoisomer].

Purification by two successive flash column chromatographies on silica gel [EtOAc / petroleum

ether, 5% (1st column) and 2% (2nd column)] afforded pure exo-8 (268 mg, 1.16 mmol, 24%), a

57 : 43 mixture of the endo and exo diastereoisomers of 8 (447 mg, 1.93 mmol, 41%) and pure

endo-8 (135 mg, 583 μmol, 12%)

14− sBuLi was slowly poured onto the cold inner walls of the flask rather than directly introduced into the solution.

− 12 −

Additional result: chlorine-lithium exchange without TMEDA and quench with D2O

sec-Butyllithium solution (0.99 M in cyclohexane, 1.30 equiv, 649 μmol, 656 μL) was added

dropwise, at –78 °C, to a solution of tert-butyl 7,7-dichloro-2-azabicyclo[4.1.0]heptane-2-

carboxylate 2b (1.00 equiv, 500 μmol, 133 mg) in Et2O (2.0 mL). After 30 min of stirring

at 78 °C, D2O (1.0 mL) was added and the reaction mixture was allowed to warm to 20 °C.

H2O (5.0 mL) and AcOH (2.0 mL) were then added and the mixture was extracted with Et2O

(3 × 5 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated

under reduced pressure to afford a yellow oil (163 mg). Analysis of the crude product by 1H NMR spectroscopy showed that the starting material had been entirely converted into tert-

butyl 7-chloro-7-deuterio-2-azabicyclo[4.1.0]heptane-2-carboxylate 8 [dr 68 : 32 in favour of the

exo diastereoisomer]. Purification by flash column chromatography on silica gel (EtOAc /

petroleum ether, gradient from 2 to 20%) afforded a 65 : 35 mixture of exo-8 (82%-d) and

endo-8 (66%-d) (27.0 mg, 116 μmol, 23%).

Additional result: radical reduction

A solution of tert-butyl 7,7-dichloro-2-azabicyclo[4.1.0]heptane-2-carboxylate 2b (1.00 equiv,

364 μmol, 97.0 mg) and triphenyltin hydride (1.10 equiv, 401 μmol, 141 mg) in benzene

(0.5 mL) was heated at reflux for 10 minutes. Azobisisobutyronitrile (5.0 mol%, 18 μmol,

3.0 mg) was then added and the mixture was stirred at reflux for a further 4 h. After cooling with

an ice bath, the solution was diluted with EtOAc (20 mL) and washed with 10% aqueous KF

solution (20 mL). The mixture was filtered, washed with brine (10 mL), dried over MgSO4,

filtered again and concentrated under reduced pressure to afford a white mixture of solid and oil

(101 mg). Analysis of the crude product by 1H NMR spectroscopy showed that the starting

material had been almost entirely converted into tert-butyl-7-chloro-2-azabicyclo[4.1.0]heptane-

2-carboxylate 8 [dr 75 : 25 in favour of the endo diastereoisomer]. Purification by flash column

chromatography on silica gel (EtOAc / petroleum ether, gradient from 0 to 7%) afforded

essentially pure endo-8 as a single diastereoisomer (16.8 mg, 72.5 μmol, 20%).15

15− This procedure is adapted from A. Pozo-Rodrigálvarez, A. Gradillas, J. Serrano, A. P. Fernández, R. Martínez-

Murillo, J. Pérez-Castells, Eur. J. Med. Chem. 2012, 54, 439−446.

− 13 −

Relative configuration of the carbon centre attached to the chlorine atom of 8

In cyclopropane systems, 3J coupling constant values are typically lower for protons in trans

relative configuration than for cis protons.16

Based on this knowledge, the relative configuration

of the chiral centre bearing the chlorine atom was determined by measuring 3J between the

protons attached to the cyclopropane sub-unit of both diastereoisomers of 8. Comparison of the

values measured is consistent with the trans relationship of the α-Cl proton with the two other

cyclopropane protons in exo-8 and with the all-cis relationship in endo-8.

16− D. J. Patel, M. E. H. Howden, J. D. Roberts, J. Am. Chem. Soc. 1963, 85, 3218–3223.

− 14 −

II. Preparation of the cyclopropylammonium salts

6,6-Dichloro-2-azoniabicyclo[3.1.0]hexane chloride 3a

12 M HCl aqueous solution (10.0 equiv, 23.8 mmol, 1.98 mL) was added dropwise to a

vigorously stirred solution of tert-butyl 6,6-dichloro-2-azabicyclo[3.1.0]hexane-2-carboxylate 2a

(1.00 equiv, 2.38 mmol, 601 mg) in EtOAc (10 mL). After 1 h of stirring, the solution was

concentrated under reduced pressure and dried under high vacuum to afford pure 6,6-dichloro-2-

azoniabicyclo[3.1.0]hexane chloride 3a (411 mg, 2.18 mmol, 91%).

7,7-Dichloro-2-azoniabicyclo[4.1.0]heptane chloride 3b

Run 1: 12 M HCl aqueous solution (10.0 equiv, 24.4 mmol, 2.03 mL) was added dropwise to a

vigorously stirred solution of tert-butyl 7,7-dichloro-2-azabicyclo[4.1.0]heptane-2-carboxylate

2b (1.00 equiv, 2.44 mmol, 650 mg) in EtOAc (10 mL). After 2 h of stirring, the solution was

concentrated under reduced pressure, washed with a small amount of Et2O, and dried under high

vacuum to afford pure 7,7-dichloro-2-azoniabicyclo[4.1.0]heptane chloride 3b (470 mg, 2.32

mmol, 95%).

Runs 2−7: 12 M HCl aqueous solution (5.00 equiv, 2.46 mmol, 205 μL) was added dropwise to

a vigorously stirred solution of 2b (1.00 equiv, 492 μmol, 131 mg) in CH2Cl2 (3.0 mL). After 16

h of stirring, the solution was concentrated under reduced pressure to afford pure 3b (88−96 mg,

435−474 μmol, 88−96%).

Run 8: 12 M HCl aqueous solution (5.0 equiv, 18.8 mmol, 1.57 mL) was added dropwise to a

vigorously stirred solution of 2b (1.00 equiv, 3.76 mmol, 1.00 g) in CH2Cl2 (8.0 mL). After 16 h

of stirring at 20 °C, the solution was concentrated under reduced pressure. The residue was

washed with a small amount of Et2O (2 × 4.0 mL) and dried under high vacuum to afford pure

3b (724 mg, 3.58 mmol, 95%).

− 15 −

7,7-Dibromo-2-azoniabicyclo[4.1.0]heptane chloride 3c

12 M HCl aqueous solution (10.0 equiv, 4.51 mmol, 376 μL) was added dropwise to a

vigorously stirred solution of tert-butyl 7,7-dibromo-2-azabicyclo[4.1.0]heptane-2-carboxylate

2c (1.00 equiv, 451 μmol, 161 mg) in EtOAc (1.5 mL). After 2 h of stirring, the solution was

concentrated under reduced pressure, washed with a small amount of Et2O, and dried under high

vacuum to afford pure 7,7-dibromo-2-azoniabicyclo[4.1.0]heptane chloride 3c (118 mg, 405

μmol, 90%).

6,6-Dichloro-1-methyl-2-azoniabicyclo[3.1.0]hexane chloride 3d

12 M HCl aqueous solution (10.0 equiv, 7.14 mmol, 595 μL) was added dropwise to a

vigorously stirred solution of tert-butyl 7,7-dichloro-2-azabicyclo[4.1.0]heptane-2-carboxylate

2d (1.00 equiv, 714 μmol, 190 mg) in EtOAc (2.0 mL). After 1 h of stirring, the solution was

concentrated under reduced pressure and dried under high vacuum to afford pure 6,6-dichloro-1-

methyl-2-azoniabicyclo[3.1.0]hexane chloride 3d (130 mg, 642 μmol, 90%).

7,7-Dichloro-1-methyl-2-azoniabicyclo[4.1.0]heptane chloride 3e

12 M HCl aqueous solution (10.0 equiv, 14.3 mmol, 1.19 mL) was added dropwise to a

vigorously stirred solution of tert-butyl 7,7-dichloro-1-methyl-2-azabicyclo[4.1.0]heptane-2-

carboxylate 2e (1.00 equiv, 1.43 mmol, 400 mg) in EtOAc (5.0 mL). After 2 h of stirring, the

solution was concentrated under reduced pressure, washed with a small amount of Et2O, and

dried under high vacuum to afford pure 7,7-dichloro-1-methyl-2-azoniabicyclo[4.1.0]heptane

chloride 3e (281 mg, 1.30 mmol, 91%).

− 16 −

(1R*,2R*,6R*)-7,7-Dichloro-2-azoniabicyclo[4.1.0]heptan-5-ol chloride 3f

Run 1: 12 M HCl aqueous solution (5.0 equiv, 1.85 mmol, 154 μL) was added dropwise to a

vigorously stirred solution of tert-butyl (1R*,5R*,6R*)-5-acetoxy-7,7-dichloro-2-

azabicyclo[4.1.0]heptane-2-carboxylate 2f (1.00 equiv, 370 μmol, 120 mg) in CH2Cl2 (2.0 mL).

After 24 h of stirring, the solution was concentrated under reduced pressure and the residue was

taken in CH2Cl2 (2.0 mL) and water (2.0 mL). The organic layer was removed and the aqueous

phase was concentrated to dryness under reduced pressure to afford fairly pure (1R*,5R*,6R*)-

7,7-dichloro-2-azoniabicyclo[4.1.0]heptan-5-ol chloride 3f (58.0 mg, 315 μmol, 85%).

Run 2: 12 M HCl aqueous solution (6.0 equiv, 12.0 mmol, 1.00 mL) was slowly added to a

vigorously stirred solution of 2f (1.00 equiv, 2.00 mmol, 648 mg) in CH2Cl2 (10 mL). After 16 h

of stirring, the solution was concentrated under reduced pressure to afford fairly pure 3f (478 mg,

quantitative yield).

(1R*,6S*,7R*)-7-Chloro-2-azoniabicyclo[4.1.0]heptane chloride exo-9

Run 1: 12 M HCl aqueous solution (10.0 equiv, 3.69 mmol, 307 μL) was added to a vigorously

stirred solution of tert-butyl (1R*,6S*,7R*)-7-chloro-2-azabicyclo[4.1.0]heptane-2-carboxylate

exo-8 (1.00 equiv, 369 μmol, 85.4 mg) in CH2Cl2 (2.0 mL). After 18 h of stirring, the solution

was concentrated under reduced pressure to afford pure (1R*,6S*,7R*)-7-chloro-2-

azoniabicyclo[4.1.0]heptane chloride exo-9 (62.4 mg, quantitative yield).


vigorously stirred solution of exo-8 (1.00 equiv, 575 μmol, 133 mg) in CH2Cl2 (2.0 mL). After

16 h of stirring at 20 °C, the solution was concentrated under reduced pressure. The residue was

washed with a small amount of Et2O and dried under high vacuum to afford pure exo-9 (96.6 mg,

575 μmol, quantitative yield).

− 17 −

(1R*,6S*,7S*)-7-Chloro-2-azoniabicyclo[4.1.0]heptane chloride endo-9


vigorously stirred solution of tert-butyl (1R*,6S*,7S*)-7-chloro-2-azabicyclo[4.1.0]heptane-2-

carboxylate endo-8 (1.00 equiv, 154 μmol, 35.6 mg) in EtOAc (1.0 mL). After 4 h of stirring, the

solution was concentrated under reduced pressure, washed with a small amount of Et2O, and

dried under high vacuum to afford pure (1R*,6S*,7S*)-7-chloro-2-azoniabicyclo[4.1.0]heptane

chloride endo-9 (20.2 mg, 120 μmol, 78%).


vigorously stirred solution of endo-8 (1.00 equiv, 255 μmol, 59.0 mg) in CH2Cl2 (2.0 mL). After

18 h of stirring, the solution was concentrated under reduced pressure and dried under high

vacuum to afford pure endo-9 (42.6 mg, 253 μmol, 99%).


vigorously stirred solution of endo-8 (1.00 equiv, 575 μmol, 133 mg) in CH2Cl2 (2.0 mL). After

16 h of stirring at 20 °C, the solution was concentrated under reduced pressure. The residue was

washed with a small amount of Et2O and dried under high vacuum to afford pure endo-9

(96.6 mg, 575 μmol, quantitative yield).

− 18 −

III. Transformations of the haloaminocyclopropane salts

General procedure B: reactions of the cyclopropylammonium salts with aldehydes and

ketones under reductive amination conditions.

Sodium triacetoxyborohydride (2.40 equiv, 240 μmol, 50.9 mg) was added at 20 °C to a solution

of aldehyde or ketone (1.00 equiv, 100 μmol) and cyclopropylammonium chloride (1.00 equiv,

100 μmol) in dry CH2Cl2 (1.0 mL). After 15 h of stirring at r.t., saturated NaHCO3 aqueous

solution (15 mL) was added. The mixture was extracted with CH2Cl2 (2 × 15 mL). The

combined organic layers were dried over Na2SO4, filtered and concentrated under reduced

pressure to afford the crude product, which was then purified by flash column chromatography

on silica gel (typically, a few drops of Et3N were added to the eluents used).

1-Benzyl-5-chloro-3,6-dihydro-2H-pyridine 5aa

General procedure B was applied using benzaldehyde (1.00 equiv, 100 μmol, 10.2 μL) and 6,6-

dichloro-2-azoniabicyclo[3.1.0]hexane chloride 3a (1.00 equiv, 100 μmol, 18.8 mg). The crude

product, a yellow oil (22.8 mg), was purified by flash column chromatography on silica gel

(EtOAc / petroleum ether, gradient from 0 to 2%) to afford pure 1-benzyl-5-chloro-3,6-dihydro-

2H-pyridine 5aa (13.8 mg, 66.4 μmol, 66%).

5-Chloro-1-[(E)-cinnamyl]-3,6-dihydro-2H-pyridine 5ab

General procedure B was applied using trans-cinnamaldehyde (1.00 equiv, 100 μmol, 12.6 μL)

and 6,6-dichloro-2-azoniabicyclo[3.1.0]hexane chloride 3a (1.00 equiv, 100 μmol, 18.8 mg). The

crude product, a dark yellow oil (26.6 mg), was purified by two flash column chromatographies

on silica gel (EtOAc / petroleum ether, gradient from 0 to 10%) to afford pure 5-chloro-1-[(E)-

cinnamyl]-3,6-dihydro-2H-pyridine 5ab (15.8 mg, 67.5 μmol, 67%).

− 19 −

3-((3-Chloro-5,6-dihydropyridin-1(2H)-yl)methyl)-1H-indole 5ac

Run 1: General procedure B was applied using indole-3-carboxaldehyde (1.00 equiv,

100 μmol, 14.5 mg) and 6,6-dichloro-2-azoniabicyclo[3.1.0]hexane chloride 3a (1.00 equiv,

100 μmol, 18.8 mg). The crude product, a dark yellow oil (28.2 mg), was purified by flash

column chromatography on silica gel (EtOAc / petroleum ether, gradient from 0 to 30%) to

afford pure 3-((3-chloro-5,6-dihydropyridin-1(2H)-yl)methyl)-1H-indole 5ac (20.4 mg, 82.6

μmol, 83%).

Run 2: The same procedure was applied. The crude product, a yellow oil (28.2 mg), was

purified by flash column chromatography on silica gel (EtOAc / petroleum ether, gradient from

0 to 30%) to afford pure 5ac (18.6 mg, 75.3 μmol, 75%).

5-Chloro-1-(cyclohexylmethyl)-3,6-dihydro-2H-pyridine 5ad

General procedure B was applied using cyclohexanecarboxaldehyde (1.00 equiv, 100 μmol,

12.1 μL) and 6,6-dichloro-2-azoniabicyclo[3.1.0]hexane chloride 3a (1.00 equiv, 100 μmol,

18.8 mg). The crude product, a dark yellow oil (21.8 mg), was purified by flash column

chromatography on silica gel (EtOAc / petroleum ether, gradient from 0 to 2%) to afford pure 5-

chloro-1-(cyclohexylmethyl)-3,6-dihydro-2H-pyridine 5ad (16.8 mg, 78.5 μmol, 78%).

5-Chloro-1-cyclohexyl-3,6-dihydro-2H-pyridine 5ae

General procedure B was applied using cyclohexanone (1.00 equiv, 100 μmol, 10.4 μL) and

6,6-dichloro-2-azoniabicyclo[3.1.0]hexane chloride 3a (1.00 equiv, 100 μmol, 18.8 mg). The

crude product, a pale yellow oil (15.8 mg). Analysis by 1H NMR spectroscopy showed that this

crude product contained a 78 : 22 mixture of 5-chloro-1-cyclohexyl-3,6-dihydro-2H-pyridine 5ae

and (3E)-3-(chloromethylene)-1-cyclohexyl-pyrrolidine 7ae. Purification by flash column

− 20 −

chromatography on silica gel (EtOAc / petroleum ether, gradient from 0 to 10%) afforded pure

5ae (12.6 mg, 63.0 μmol, 63%).

2-Benzyl-7,7-dichloro-2-azabicyclo[4.1.0]heptane 4ba

Sodium triacetoxyborohydride (1.50 equiv, 150 μmol, 31.8 mg) was added at 20 °C to a solution

of benzaldehyde (1.00 equiv, 100 μmol, 10.2 μL) and 7,7-dichloro-2-

azoniabicyclo[4.1.0]heptane chloride 3b (1.00 equiv, 100 μmol, 20.3 mg) in CH2Cl2 (1.0 mL).

After 1 h of stirring at 20 °C, saturated NaHCO3 aqueous solution (15 mL) was added. The

mixture was extracted with CH2Cl2 (2 × 15 mL). The combined organic layers were dried over

Na2SO4, filtered and concentrated under reduced pressure to afford a brown oil (29.6 mg).

Analysis by 1H and

13C NMR spectroscopy revealed the presence of 2-benzyl-7,7-dichloro-2-

azabicyclo[4.1.0]heptane 4ba, 1-benzyl-6-chloro-2,3,4,7-tetrahydroazepine 5ba, 1-benzyl-3-

(dichloromethyl)piperidine and 1-benzyl-6-chloro-2,3-dihydroazepine in 76 : 08 : 04 : 12 ratio

approximately.

Other runs: the following table sums up the results of selected experiments performed with the

same substrates, showing that 5-benzyl-7,7-dichloro-5-azabicyclo[4.1.0]heptane 4ba is the

primary product of the reaction, that is then slowly converted into the final products observed

(half-life around 2 h under the reaction conditions typically applied).

− 21 −

Run NaBH(OAc)3 Reaction time (h) Product ratio

4ba / 5ba / 7ba / 16ba / 17ba

1 old batch,a 1.50 equiv 1 76 : 08 : 00 : 04 : 12

2 old batch,a 2.40 equiv 1.5 52 : 21 : 11 : 15 : 01

b

3 old batch,a 2.40 equiv 16 00 : 55 : 19 : 26 : 00

4 “aged” old batch,c 3.3 equiv 1 60 : 19 : 15 : 06 : 00

2.75 30 : 36 : 28 : 06 : 00

3.75 22 : 40 : 31 : 06 : 00

4.25 12 : 44 : 36 : 08 : 00

a This batch had been used before. The bottle had been opened for the first time at an unknown date.

b After work-

up, purification by flash column chromatography on silica gel (EtOAc / petroleum ether, gradient from 0 to 2%)

afforded rather impure 5-benzyl-7,7-dichloro-5-azabicyclo[4.1.0]heptane (4.6 mg, 17.9 μmol, 18%). c The same

bottle was employed as in the preceding runs, but after more than one year. It is possible that it was misused or not

properly closed in the meantime.

1-Benzyl-6-chloro-2,3,4,7-tetrahydroazepine 5ba

General procedure B was applied on a five-fold scale using benzaldehyde (1.00 equiv,

500 μmol, 50.8 μL) and 7,7-dichloro-2-azoniabicyclo[4.1.0]heptane chloride 3b (1.00 equiv,

500 μmol, 101 mg). The crude product (97.0 mg), was analysed by 1H NMR spectroscopy,

showing the presence of 1-benzyl-6-chloro-2,3,4,7-tetrahydroazepine 5ba, 1-benzyl-3-

(chloromethylene)-piperidine 7ba (E / Z ≈ 56 : 44), 1-benzyl-3-(dichloromethyl)piperidine 16ba

and 1-benzyl-6-chloro-2,3-dihydroazepine 17ba in 59 : 08 : 31 : 02 ratio approximately, as

measured by integration of characteristic signals. Purification by flash column chromatography

on silica gel (EtOAc / petroleum ether, gradient from 2 to 8%) afforded pure 1-benzyl-6-chloro-

− 22 −

2,3,4,7-tetrahydroazepine 5ba (60.0 mg, 271 μmol, 54%) and pure 1-benzyl-3-

(dichloromethyl)piperidine 16ba (26.0 mg, 101 μmol, 20%).

Other runs: the following table sums up the results of selected experiments performed with the

same substrates. The line highlighted in blue indicates the particular run described in detail in the

preceding paragraph.

Run Conditions Product ratio

5ba / 8ba / 16ba / 17ba

1 NaBH(OAc)3 (old batch,a 2.4 equiv), 16 h 55 : 19 : 26 : 00

b

2 NaBH(OAc)3 (old batch,

a 2.4 equiv)

ClCH2CH2Cl instead of CH2Cl2, 60 h 54 : 26 : 17 : 03

3 NaBH(OAc)3 (“aged” old batch,c 2.4 equiv), 16 h 61 : 28 : 10 : 00

d


e

5 NaBH(OAc)3 (“aged” old batch,

c 3.3 equiv)

MS 4Å, 16 h 54 : 37 : 09 : 00


7 NaBH(OAc)3 (new batch,f 2.4 equiv), 16 h 59 : 08 : 31 : 02

g

8 NaBH(OAc)3 (new batch,

h 2.4 equiv)

MS 4Å, 16 h 44 : 21 : 24 : 11

a This batch had been used before. The bottle had been opened for the first time at an unknown date.

b 1-Benzyl-6-

chloro-2,3,4,7-tetrahydroazepine was isolated in 50% yield. c The same bottle was employed as in the preceding

runs, but after more than one year. It is possible that it was misused or not properly closed in the meantime. d The

1H

NMR spectrum of the crude product was much messier than the one recorded after run 2. e 1-Benzyl-6-chloro-

2,3,4,7-tetrahydroazepine was isolated in 30% yield only. f A new bottle was purchased and opened just before use.

g 1-Benzyl-6-chloro-2,3,4,7-tetrahydroazepine was isolated in 54% yield.

h Experiment performed immediately after

the preceding one.

Conclusions: the good quality of the NaBH(OAc)3 reagent is essential for best results to be

obtained; yields drop significantly when degraded reagent is used. In that case, employing larger

amounts of NaBH(OAc)3 partly makes up for the problem. It is observed that with “good”

NaBH(OAc)3, the use of 4 Å molecular sieves increases the amount of by-product 17ba formed,

essentially at the expense of 5ba.

− 23 −

3-[(6-Chloro-2,3,4,7-tetrahydroazepin-1-yl)methyl]-1H-indole 5bc

General procedure B was applied using indole-3-carboxaldehyde (1.00 equiv, 100 μmol, 14.5

mg) and 7,7-dichloro-2-azoniabicyclo[4.1.0]heptane chloride 3b (1.00 equiv, 100 μmol, 20.3

mg). The crude product, a dark yellow oil (24.8 mg) was analysed by 1H NMR, revealing the

presence of 3-[(6-chloro-2,3,4,7-tetrahydroazepin-1-yl)methyl]-1H-indole as a minor component

in a mixture of unidentified compounds. No purification was attempted.

1H NMR spectrum of the crude product (CDCl3, 400 MHz).

6-Chloro-1-(cyclohexylmethyl)-2,3,4,7-tetrahydroazepine 5bd

General procedure B was applied using cyclohexanecarboxaldehyde (1.00 equiv, 100 μmol,

12.1 μL) and 7,7-dichloro-2-azoniabicyclo[4.1.0]heptane chloride 3b (1.00 equiv, 100 μmol,

− 24 −

20.3 mg). The crude product, a brown oil (26.8 mg), was analysed by 1H NMR spectroscopy to

reveal the presence of 6-chloro-1-(cyclohexylmethyl)-2,3,4,7-tetrahydroazepine 5bd, 3-

(chloromethylene)-1-(cyclohexylmethyl)piperidine 7bd (E / Z ≈ 56 : 44), 1-(cyclohexylmethyl)-

3-(dichloromethyl)piperidine 16bd and 6-chloro-1-(cyclohexylmethyl)-2,3-dihydroazepine 17bd

in 41 : 35 : 19 : 05 ratio approximately, as measured by integration of characteristic signals.


from 0 to 2%) afforded pure 5bd (6.6 mg, 29 μmol, 29%).


6-Chloro-1-cyclohexyl-2,3,4,7-tetrahydroazepine 5be

Run 1: General procedure B was applied using cyclohexanone (1.00 equiv, 100 μmol,

10.4 μL) and 7,7-dichloro-2-azoniabicyclo[4.1.0]heptane chloride 3b (1.00 equiv, 100 μmol,

20.3 mg). The crude product, a brown oil (23.6 mg), was analysed by 1H NMR spectroscopy to

reveal the presence of 6-chloro-1-cyclohexyl-2,3,4,7-tetrahydroazepine 5be, 3-

(chloromethylene)-1-cyclohexyl-piperidine 7be (E / Z ≈ 54 : 46), 1-cyclohexyl-3-

(dichloromethyl)piperidine 16be and 6-chloro-1-cyclohexyl-2,3-dihydroazepine 17be in 20 : 65 :

12 : 03 ratio approximately, as measured by integration of characteristic signals.


from 0 to 20%) afforded pure 5be (4.5 mg, 21 μmol, 21%).

− 25 −


Run 2: General procedure B was applied on five-fold scale using cyclohexanone (1.00 equiv,

500 μmol, 51.8 μL) and 3b (1.00 equiv, 500 μmol, 101 mg). The crude product, a brown oil (109

mg), was purified by flash column chromatography on silica gel (EtOAc / petroleum ether,

gradient from 0 to 10%) to afford pure 5be (20.0 mg, 93.5 μmol, 19%).

6-Chloro-1-butyl-2,3,4,7-tetrahydroazepine 5bf

General procedure B was applied using butyraldehyde (1.00 equiv, 100 μmol, 9.0 μL) and 7,7-

dichloro-2-azoniabicyclo[4.1.0]heptane chloride 3b (1.00 equiv, 100 μmol, 20.3 mg). The crude

product, a yellow oil (26.8 mg) was analysed by 1H NMR, revealing the presence of 6-chloro-1-

butyl-2,3,4,7-tetrahydroazepine 5bf and 1-butyl-3-(dichloromethyl)piperidine 16bf (ratio

70 : 30), as well as several other compounds. Purification by flash column chromatography on

silica gel did not allow us to isolate a pure product.

− 26 −


Additional result from 3b: (6-chloro-2,3,4,7-tetrahydroazepin-1-yl)-phenyl-methanone

Sodium triacetoxyborohydride (2.40 equiv, 480 μmol, 102 mg) was added at 20 °C to a solution

of 7,7-dichloro-2-azoniabicyclo[4.1.0]heptane chloride 3b (1.00 equiv, 200 μmol, 40.5 mg) in

dry CH2Cl2 (1.0 mL). After 15 h of stirring at 20 °C, benzoyl chloride (3.00 equiv, 600 μmol,

69.6 μL) was added and the mixture was stirred at 20 °C for a further 2 h. Saturated NaHCO3

aqueous solution (15 mL) was then added. The mixture was extracted with CH2Cl2 (2 × 15 mL).

The combined organic layers were dried over MgSO4, filtered and concentrated under reduced

pressure to afford a yellow oil (49.2 mg). The crude product was purified by flash column

chromatography on silica gel (EtOAc / petroleum ether, gradient from 0 to 20%) to afford pure

(6-chloro-2,3,4,7-tetrahydroazepin-1-yl)-phenyl-methanone (17.5 mg, 74.2 μmol, 37%).

1-Benzyl-6-bromo-2,3,4,7-tetrahydroazepine 5ca


dibromo-2-azoniabicyclo[4.1.0]heptane chloride 3c (1.00 equiv, 100 μmol, 29.1 mg). The crude

product, a dark yellow oil (22.8 mg), was purified by flash column chromatography on silica gel

− 27 −

(EtOAc / petroleum ether, gradient from 0 to 5%) to afford pure 1-benzyl-6-bromo-2,3,4,7-

tetrahydroazepine 5ca (13.2 mg, 49.5 μmol, 49%).

1-Benzyl-5-chloro-6-methyl-3,6-dihydro-2H-pyridine 5da


dichloro-1-methyl-2-azoniabicyclo[3.1.0]hexane chloride 3d (1.00 equiv, 100 μmol, 20.3 mg).

The crude product, a yellow oil (18.8 mg), was purified by flash column chromatography on

silica gel (EtOAc / petroleum ether, gradient from 0 to 2%) to afford pure 1-benzyl-5-chloro-6-

methyl-3,6-dihydro-2H-pyridine 5da (9.8 mg, 44 μmol, 44%).

Additional result from 3d: 5-chloro-6-methyl-1,2,3,6-tetrahydropyridine

Sodium borohydride (3.00 equiv, 300 μmol, 11.3 mg) was added at 0 °C to a solution of 6,6-

dichloro-1-methyl-2-azoniabicyclo[3.1.0]hexane chloride 3d (1.00 equiv, 100 μmol, 20.3 mg) in

MeOH (1.0 mL). After 4 h of stirring at 0 °C, H2O (10 mL) was added and the mixture was

extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over Na2SO4,

filtered and concentrated under reduced pressure (50 mbar, bath 30 °C) to afford a yellow oil

(30.2 mg). Analysis by 1H NMR spectroscopy revealed the presence of 5-chloro-6-methyl-

1,2,3,6-tetrahydropyridine as a major component.

1-Benzyl-6-chloro-2,3,4,7-tetrahydroazepin-4-ol 5fa

General procedure B was applied on larger scale using benzaldehyde (1.00 equiv, 592 μmol,

60.2 μL) and (1R*,5R*,6R*)-7,7-dichloro-2-azoniabicyclo[4.1.0]heptan-5-ol chloride 3f

(1.00 equiv, 592 μmol, 129 mg). The crude product, a dark brown oil (150 mg), was purified by

flash column chromatography on silica gel (EtOAc / petroleum ether, gradient from 10 to 30%)

to afford pure 1-benzyl-6-chloro-2,3,4,7-tetrahydroazepin-4-ol 5fa (9.0 mg, 37.8 μmol, 6%).

− 28 −

5-Chloro-2,3-dihydropyridine 6a

An NMR sample was prepared with a few milligrams of 6,6-dichloro-2-

azoniabicyclo[3.1.0]hexane chloride 3a in CDCl3 (0.50 mL). A 1H NMR spectrum of this sample

was taken and then excess amounts of triethylamine (about 9 equivalents) were introduced in the

tube. After 5 minutes, a new analysis by 1H NMR spectroscopy revealed the complete

transformation of the starting material into 5-chloro-2,3-dihydropyridine 6a.

Note: a similar experiment was performed using excess amounts of K2CO3 instead of triethylamine.

No deprotonation of the ammonium salt was observed after 30 min at room temperature.

Conversely, using NaOH, a complex mixture was observed.

5-Chloro-6-methyl-2,3-dihydropyridine 6d

An NMR sample was prepared with a few milligrams of 6,6-dichloro-1-methyl-2-

azoniabicyclo[3.1.0]hexane chloride 3d in CDCl3 (0.50 mL). A 1H NMR spectrum of this sample

was taken and then excess amounts of triethylamine (about 6 equivalents) were introduced into

the tube. After 5 minutes, a new analysis by 1H NMR spectroscopy revealed the complete and

clean transformation of the starting material into 5-chloro-6-methyl-2,3-dihydropyridine 6d.

Note: a similar experiment was performed using excess amounts of K2CO3 instead of triethylamine.

No deprotonation of the ammonium salt was observed after 4 h at room temperature.

Conversely, using NaOH, a complex mixture was observed after 5 min of reaction.

(E)-1-Benzyl-3-(chloromethylene)-2-methyl-piperidine 7ea

Run 1: General procedure B was applied using benzaldehyde (1.00 equiv, 100 μmol, 10.2 μL)

and 7,7-dichloro-1-methyl-2-azoniabicyclo[4.1.0]heptane chloride 3e (1.00 equiv, 100 μmol,

21.7 mg). The crude product, a dark yellow oil (27.8 mg), was purified by two flash column

chromatographies on silica gel (EtOAc / petroleum ether, gradient from 0 to 5%) to afford pure

(E)-1-benzyl-3-(chloromethylene)-2-methyl-piperidine 7ea (11.3 mg, 47.9 μmol, 48%).

− 29 −

Run 2: General procedure B was applied on double scale, using benzaldehyde (1.00 equiv,

200 μmol, 20.3 μL) and 3e (1.00 equiv, 200 μmol, 43.3 mg). The crude product, a dark yellow

oil (40.8 mg), was purified by two flash column chromatographies on silica gel (EtOAc /

petroleum ether, gradient from 0 to 5%) to afford pure 7ea (21.4 mg, 90.7 μmol, 45%).

(3E)-3-(Chloromethylene)-1-[(E)-cinnamyl]-2-methyl-piperidine 7eb

General procedure B was applied using trans-cinnamaldehyde (1.00 equiv, 100 μmol, 12.6 μL)

and 7,7-dichloro-6-methyl-5-azoniabicyclo[4.1.0]heptane chloride 3e (1.00 equiv, 100 μmol,

21.7 mg). The crude product, a dark yellow oil (28.6 mg), was purified by flash column

chromatography on silica gel (EtOAc / petroleum ether, gradient from 0 to 20%) to afford pure

(3E)-3-(chloromethylene)-1-[(E)-cinnamyl]-2-methyl-piperidine 7eb (17.2 mg, 65.7 μmol, 66%).

(1R*,6S*,7R*)-2-Benzyl-7-chloro-2-azabicyclo[4.1.0]heptane exo-10

General procedure B was applied using benzaldehyde (1.00 equiv, 575 μmol, 60.0 μL) and

(1R*,6S*,7R*)-7-chloro-2-azoniabicyclo[4.1.0]heptane chloride exo-9 (1.00 equiv, 575 μmol,

96.6 mg). The crude product was analysed by NMR spectroscopy and no trace of 1-benzyl-

2,3,4,7-tetrahydroazepine 11 was observed. Purification by flash column chromatography on

silica gel (EtOAc / petroleum ether, gradient from 0 to 5%) afforded pure (1R*,6S*,7R*)-2-

benzyl-7-chloro-2-azabicyclo[4.1.0]heptane exo-10 (90.0 mg, 406 μmol, 71%).

− 30 −

1H NMR spectrum of the crude product (CDCl3, 400 MHz), displayed in black. Spectra of pure (1R*,6S*,7S*)-5-

benzyl-7-chloro-5-azabicyclo[4.1.0]heptane and 1-benzyl-5-chloro-3,6-dihydro-2H-pyridine are also presented, in

red and in green respectively, showing the absence of the latter compound in the crude product.

1-Benzyl-2,3,4,7-tetrahydroazepine 11

General procedure B was applied using benzaldehyde (1.00 equiv, 575 μmol, 60.0 μL) and

(1R*,6S*,7S*)-7-chloro-2-azoniabicyclo[4.1.0]heptane chloride endo-9 (1.00 equiv, 575 μmol,

96.6 mg). The crude product was purified by flash column chromatography on silica gel (EtOAc

/ petroleum ether, gradient from 2 to 15%) to afford pure 1-benzyl-2,3,4,7-tetrahydroazepine 11

(106 mg, 566 μmol, 98%).

1-[(1R*,6S*,7S*)-7-Chloro-2-azabicyclo[4.1.0]heptan-2-yl]-2-(3,4,5-trimethoxyphenyl)ethanone

endo-14

1 M NaOH aqueous solution (10 mL) was added to a solution of 2-(3,4,5-

trimethoxyphenyl)acetyl chloride (1.10 equiv, 274 μmol, 67.0 mg) and (1R*,6S*,7S*)-7-chloro-

2-azoniabicyclo[4.1.0]heptane chloride endo-9 (1.00 equiv, 249 μmol, 41.6 mg) in CH2Cl2

(10 mL). After 2 h of stirring at 20 °C, the organic layer was separated and the aqueous phase

− 31 −

was extracted with CH2Cl2 (2 × 10 mL). The combined organic layers were dried over MgSO4,

filtered and concentrated under reduced pressure to afford a thick pale yellow oil (74.0 mg).


from 30 to 100%) to afford pure 1-[(1R*,6S*,7S*)-7-chloro-2-azabicyclo[4.1.0]heptan-2-yl]-2-

(3,4,5-trimethoxyphenyl)ethanone endo-14 (57.6 mg, 218 μmol, 68%).

1-(2,3-Dihydroazepin-1-yl)-2-(3,4,5-trimethoxyphenyl)ethanone 15

37% HCl aqueous solution (1 drop) was added, at 20 °C, to a solution of 1-[(1R*,6S*,7S*)-7-

chloro-2-azabicyclo[4.1.0]heptan-2-yl]-2-(3,4,5-trimethoxyphenyl)ethanone endo-14

(1.00 equiv, 64.7 µmol, 22.0 mg) in DMF (1.0 mL). The mixture was heated at 150 °C for

90 minutes with a microwave reactor (power 250 W) and controlled by TLC. After cooling, H2O

(15 mL) was added and the mixture was extracted with EtOAc (3 × 10 mL). The combined

organic phases were dried over MgSO4, filtered and concentrated under reduced pressure to

afford a sticky orange oil (14.0 mg). Purification by flash column chromatography on silica gel

(EtOAc / petroleum ether, gradient from 5 to 50%) gave pure 1-(2,3-dihydroazepin-1-yl)-2-

(3,4,5-trimethoxyphenyl)ethanone 15 (10.0 mg, 33.0 µmol, 51%).

Additional result from endo-8: tert-butyl 2,3-dihydroazepine-1-carboxylate

2,4,6-Collidine (1 drop) was added, at 20 °C, to a solution of tert-butyl (1R*,6S*,7S*)-7-chloro-

2-azabicyclo[4.1.0]heptane-2-carboxylate endo-8 (1.00 equiv, 58.6 µmol, 13.6 mg) in DMF

(1.0 mL). The mixture was heated at 150 °C for 30 minutes with a microwave reactor (power

250 W). After cooling, H2O (15 mL) was added and the mixture was extracted with Et2O

(3 × 15 mL). The combined organic phases were dried over MgSO4, filtered and concentrated

under reduced pressure to afford a sticky orange oil (4.9 mg). Analysis by 1H NMR spectroscopy

revealed that this crude product contained fairly pure tert-butyl 2,3-dihydroazepine-1-

carboxylate (4.9 mg, if pure: 25.0 µmol, 43%). A slightly purer sample (about 1 mg) was

obtained by flash column chromatography on silica gel (EtOAc / petroleum ether, gradient from

0 to 2%).

− 32 −

1-[(1R*,6S*,7R*)-7-Chloro-2-azabicyclo[4.1.0]heptan-2-yl]-2-(3,4,5-trimethoxyphenyl)ethanone

exo-14

1 M NaOH aqueous solution (10 mL) was added to a solution of 2-(3,4,5-

trimethoxyphenyl)acetyl chloride (1.00 equiv, 163 μmol, 39.8 mg) and (1R*,6S*,7R*)-7-chloro-

2-azoniabicyclo[4.1.0]heptane chloride exo-9 (1.00 equiv, 163 μmol, 27.2 mg) in CH2Cl2

(10 mL). After 2 h of stirring at 20 °C, the organic layer was separated and the aqueous phase

was extracted with CH2Cl2 (2 × 10 mL). The combined organic layers were dried over MgSO4,

filtered and concentrated under reduced pressure to afford an orange mixture of solid and oil

(43.8 mg). Purification by flash column chromatography on silica gel (EtOAc / petroleum ether

50%) to afford pure 1-[(1R*,6S*,7R*)-7-chloro-2-azabicyclo[4.1.0]heptan-2-yl]-2-(3,4,5-

trimethoxyphenyl)ethanone exo-14 (34.5 mg, 102 μmol, 62%).

Attempted transformation of exo-14

The following reaction conditions were applied on 50 to 100 μmol scale, leaving the starting

material unchanged:

• pTSA (0.05 equiv), 250 W microwave irradiation, PhCl, 140 °C, 15 min.

• TfOH (1 drop), PhCl, 20 °C, 15 h.

• TfOH (1 drop), 250 W microwave irradiation, PhCl, 140 °C, 60 min.

• TfOH (1 drop), 300 W microwave irradiation, PhCl, 160 °C, 30 min.

• AgBF4 (1.5 equiv), CH2Cl2, 20 °C, 18 h.

• AgBF4 (1.5 equiv), 250 W microwave irradiation, MeCN, 100 °C, 60 min.

Synthesis of functionalised azepanes and piperidines from ...c Department of Organic Chemistry, Faculty of Chemistry, University of Łódź, Tamka 12, Łódź 91-403, Poland Experimental

Documents